Performance of Repeated Measures of (1–3)-β-D-Glucan, Mannan Antigen, and Antimannan Antibodies for the Diagnosis of Invasive Candidiasis in ICU Patients: A Preplanned Ancillary Analysis of the EMPIRICUS Randomized Clinical Trial

Abstract

Background We aimed to assess the prognostic value of repeated measurements of serum (1-3)-β-D-glucan(BDG), mannan-antigen(mannan-Ag) and anti-mannan antibodies(anti-mannan-Ab) on the occurrence of Invasive Candidiasis(IC) in a high risk non-immunocompromised population. Methods It is a preplanned ancillary analysis of the EMPIRICUS Randomized Clinical Trial, including non-immunocompromised critically ill patients with ICU-acquired sepsis, multiple Candida colonization, multiple organ failure, exposed to broad-spectrum antibacterial agents. BDG(>80 and >250 pg/mL), mannan-Ag(>125 pg/mL) and anti-mannan-Ab(>10 AU) were collected repeatedly. We used cause-specific hazard models. Biomarkers were assessed at baseline in the whole cohort(cohort 1). Baseline covariates and/or repeated measurements and/or increased of biomarkers were then studied in the subgroup of patients who were still alive at day 3 and free of IC(cohort 2). Results 234 patients were included and 215 were still alive and free of IC at day 3. IC developed in 27(11.5%) and day-28 mortality was 29.1%. Finally, only BDG>80 pg/ml at inclusion was associated with an increased risk of IC(CSHR[IC]=4.67, CI95% 1.61-13.5) but not death (CSHR[death]=1.20, CI95% 0.71-2.02). Conclusions Among high risk patients, a first measurement of BDG over 80 pg/mL was strongly associated with the occurrence of IC. Neither a cut off-of 250 pg/mL nor repeated measurements of fungal biomarkers seemed to be useful to predict the occurrence of IC. The cumulative risk of IC in the placebo group if BDG>80 pg/ml was 25.39% questioning about the potential interest of empirical therapy in this subgroup.

Intensive Care Antifungal Stewardship Programme Based on T2Candida PCR and Candida Mannan Antigen: A Prospective Study

“…In a recent retrospective study of the EMPERICUS randomized clinical performance of BDG, the mannan-Ag, and mannan antibody were assessed in a mixed medical/surgical ICU population with an IC incidence of 11.5%. In this study, in which a majority of patients were non-surgical, MAg had relatively good NPV but poor specificity for prediction of IC with a sensitivity/specificity/PPV/NPV of 88%/15%/14%/89% [6,38].…”

(1 → 3)-β-d-Glucan-guided antifungal therapy in adults with sepsis: the CandiSep randomized clinical trial

“…A sensitivity as low as 20% has been observed in several studies [35] and may be associated with a low pathogen load [39]. Current data rather suggest that BDG can be used as a surrogate for withdrawal of empirically started antifungal treatment rather than early initiation [10,11,42]. Our sample size calculation was based on a mortality rate of 49.8% considering the high-risk profile of this patient population [14].…”

“…A sensitivity as low as 20% has been observed in several studies [ 35 ] and may be associated with a low pathogen load [ 39 ]. Current data rather suggest that BDG can be used as a surrogate for withdrawal of empirically started antifungal treatment rather than early initiation [ 10 , 11 , 42 ].…”

Diagnosis and Treatment of Invasive Candidiasis

“…Most Candida antigens demonstrated low concentrations and were rapidly cleared from the patients’ blood. The cell wall antigens mannan and β-D-glucan appeared to be promising targets [ 67 , 106 , 107 ]. The first tests to be introduced into practice were immune assays capable of detecting mannan and anti-mannan antibodies.…”